Process chemistry
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Nov 29, 2019
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About This Presentation
SHIKHA POPALI AND HARSHPAL SINGH WAHI PRESENTS PHARMACEUTICAL PROCESS CHEMISTRYT THE MORE INTERESETED TOPIC LIKED BY STUDENTS
Slide Content
Pharmaceutical
Process Chemistry
SHIKHA D. POPALI
HARSHPAL SINGH WAHI
GURUNANAK COLLEGE OF PHARMACY
Process Chemistry
SHIKHA D. POPALI
HARSHPAL SINGH WAHI
GURUNANAK COLLEGE OF PHARMACY
INTRODUCTION
2
“Drug”–a compound that interacts with a biological
molecule, triggering a physiological effect.
Drugs (active pharmaceutical ingredients) can be classified
into 4 groups depending on their origin;
1) Natural products
2) Fermentation products
3) Semi-synthetics –substances produced by partial
synthesis
4) Completely synthetic products
2
“Drug”–a compound that interacts with a biological
molecule, triggering a physiological effect.
Drugs (active pharmaceutical ingredients) can be classified
into 4 groups depending on their origin;
1) Natural products
2) Fermentation products
3) Semi-synthetics –substances produced by partial
synthesis
4) Completely synthetic products
Background
Average cost of developing a drug was $500 million in 1999 and
takes 12-25 years usually.
The chances of a candidate drug that is identified becoming
approved is approximately 1 in 10,000. (For every 10,000 trial
compounds, 20 reach trials on animals, 10 reach clinical trials on
humans and 1 gets FDA approval)
Discovery stage (research labs) involves preparation of potential drug
compound on 10 mg to 10 g scale. Toxicology tests are carried out on
this material. If these are successful, greater quantities of the
compound will be required for clinical trials.
At this stage, development work begins.
-Immediate goal –to produce clinical trial material.
-Longer term goal–to develop a commercially viable scaled-up
validated process.
3
Average cost of developing a drug was $500 million in 1999 and
takes 12-25 years usually.
The chances of a candidate drug that is identified becoming
approved is approximately 1 in 10,000. (For every 10,000 trial
compounds, 20 reach trials on animals, 10 reach clinical trials on
humans and 1 gets FDA approval)
Discovery stage (research labs) involves preparation of potential drug
compound on 10 mg to 10 g scale. Toxicology tests are carried out on
this material. If these are successful, greater quantities of the
compound will be required for clinical trials.
At this stage, development work begins.
-Immediate goal –to produce clinical trial material.
-Longer term goal–to develop a commercially viable scaled-up
validated process.
3
Terminology
Development–covers all work between research and
production (e.g. analytical, chemical, formulation) and
continues when production begins.
Scale-up–process of going from laboratory preparation to
whatever scale of manufacture is required to satisfy the
market demand (usually 1,000 to 50,000 L range)
Technology Transfer
-Transfer between manufacturing sites
-Transfer within a manufacturing site
(Partnerships for collaborative R & D)
4
Development–covers all work between research and
production (e.g. analytical, chemical, formulation) and
continues when production begins.
Scale-up–process of going from laboratory preparation to
whatever scale of manufacture is required to satisfy the
market demand (usually 1,000 to 50,000 L range)
Technology Transfer
-Transfer between manufacturing sites
-Transfer within a manufacturing site
(Partnerships for collaborative R & D)
4
Process chemistry
5
Process chemistry involves development of practical,
safe and cost effective processes for the synthesis of
compounds selected to progress from
research/discovery to a larger scale.
Within the pharmaceutical industry synthetic routes developed within
medicinal chemistry often have to be completely redesigned by process
chemists, and this is in part due to their differing requirements.
The differences between medicinal and process chemistry and the multitude
of factors that need to be taken into consideration when scaling up a
chemical process.
5
Process chemistry involves development of practical,
safe and cost effective processes for the synthesis of
compounds selected to progress from
research/discovery to a larger scale.
Within the pharmaceutical industry synthetic routes developed within
medicinal chemistry often have to be completely redesigned by process
chemists, and this is in part due to their differing requirements.
The differences between medicinal and process chemistry and the multitude
of factors that need to be taken into consideration when scaling up a
chemical process.
Medicinal
chemistry Vs
For medicinal chemists diversity
and flexibility of a route is
important.
They synthesise a wide range of
analogues of a lead compound
on a small scale (20 mg) for
testing in order to increase
activity, reduce side effects and
to produce an API that may be
easily and efficiently
administered to the patient.
For this the compound must
have the right properties in
terms of activity, toxicity,
solubility, pharmacokinetics and
pharmacodynamics.
6
In contrast, process chemistry
involves development of
practical, safe and cost effective
processes for the synthesis of
compounds on a larger scale
(kg to several tonnes) that have
been selected to progress from
medicinal chemistry.
They generally therefore work
on a single target molecule and
define the best route to that
target.
Process chemistry
chemistry Vs
For medicinal chemists diversity
and flexibility of a route is
important.
They synthesise a wide range of
analogues of a lead compound
on a small scale (20 mg) for
testing in order to increase
activity, reduce side effects and
to produce an API that may be
easily and efficiently
administered to the patient.
For this the compound must
have the right properties in
terms of activity, toxicity,
solubility, pharmacokinetics and
pharmacodynamics.
6
In contrast, process chemistry
involves development of
practical, safe and cost effective
processes for the synthesis of
compounds on a larger scale
(kg to several tonnes) that have
been selected to progress from
medicinal chemistry.
They generally therefore work
on a single target molecule and
define the best route to that
target.
Process chemistry
Process chemistry
7
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
7
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
Process chemistry
8
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
8
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
Process chemistry
9
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
9
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
DOE in Process Parameters
10
With the most recent ICH and
FDA guidances endorsing a new
paradigm of process validation
based more on process
understanding and control of
parameters and less on product
testing.
After using process knowledge to relate the attributes to each
process unit operation, the inputs and outputs of each unit
operation are defined to determine process parameters and in-
process controls.
10
With the most recent ICH and
FDA guidances endorsing a new
paradigm of process validation
based more on process
understanding and control of
parameters and less on product
testing.
After using process knowledge to relate the attributes to each
process unit operation, the inputs and outputs of each unit
operation are defined to determine process parameters and in-
process controls.
DOE in Process Parameters
11
ICH Q8(R2) provides the following definitions using the term critical:
•Critical process parameter (CPP).A process parameter whose variability has an impact on a critical quality
attribute and, therefore, should be monitored or controlled to ensure the process produces the desired quality.
•Critical quality attribute (CQA).A physical, chemical, biological, or microbiological property or
characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product
quality.
The definition for CPP states that a parameter is considered critical when its
variability has an impact on a CQA.
The amount of impact is not defined, which leads to the question, does even
a small impact to a CQA mean that the parameter is critical?
11
ICH Q8(R2) provides the following definitions using the term critical:
•Critical process parameter (CPP).A process parameter whose variability has an impact on a critical quality
attribute and, therefore, should be monitored or controlled to ensure the process produces the desired quality.
•Critical quality attribute (CQA).A physical, chemical, biological, or microbiological property or
characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product
quality.
The definition for CPP states that a parameter is considered critical when its
variability has an impact on a CQA.
The amount of impact is not defined, which leads to the question, does even
a small impact to a CQA mean that the parameter is critical?
DOE in Process Parameters
12
It is not difficult to imagine the example of an extreme shift of a
process parameter having a minor impact on a CQA, whether
measurable or not.
Extreme temperatures can destroy many pharmaceutical
products; however, if a process inherently cannot produce such
temperatures, is temperature still considered to be critical and,
therefore, required to be monitored and controlled?
12
It is not difficult to imagine the example of an extreme shift of a
process parameter having a minor impact on a CQA, whether
measurable or not.
Extreme temperatures can destroy many pharmaceutical
products; however, if a process inherently cannot produce such
temperatures, is temperature still considered to be critical and,
therefore, required to be monitored and controlled?
DOE in Process Parameters
13
When these definitions are strictly interpreted, then one of two
extremes would be:
• Every quality attribute is critical (they all ensure product
quality); every parameter is critical (product cannot be made
without controlling them)
• No parameter is critical because if they are controlled, all
quality attributes will pass specifications.
Reality lies somewhere between these extremes.
Logic and common sense dictate that additional criteria must be
necessary to aid in determining criticality.
There is great value in understanding not only if a
parameter/attribute is critical (i.e., has an impact), but also how
much impact the parameter/attribute has.
13
When these definitions are strictly interpreted, then one of two
extremes would be:
• Every quality attribute is critical (they all ensure product
quality); every parameter is critical (product cannot be made
without controlling them)
• No parameter is critical because if they are controlled, all
quality attributes will pass specifications.
Reality lies somewhere between these extremes.
Logic and common sense dictate that additional criteria must be
necessary to aid in determining criticality.
There is great value in understanding not only if a
parameter/attribute is critical (i.e., has an impact), but also how
much impact the parameter/attribute has.
Process chemistry
14
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
14
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
Process chemistry
15
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
15
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
Process chemistry
16
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
16
The key stages in process chemistry for the development of an active
pharmaceutical ingredient
Term synthesis means in Greek
“put together”.
Synthetic chemistry is the “art” of building-up
complex molecular structures of compounds
putting together smaller, easily accessible
compounds.
17Synthetic Strategy
“put together”.
Synthetic chemistry is the “art” of building-up
complex molecular structures of compounds
putting together smaller, easily accessible
compounds.
17Synthetic Strategy
Synthetic Strategy
18
The construction of a complex organic structure, defined
target molecule, requires first of all the identification of the
smaller fragments that can be used to build-up the final target.
In the case of oligomers such as peptides,
oligosaccharides or oligonucleotides, the choice is
obvious: the constituent monomers are the building
blocks, and the synthesis requires the junction of those
monomers by condensation.
Two functional groups, one for each monomer, are involved
in the reaction
18
The construction of a complex organic structure, defined
target molecule, requires first of all the identification of the
smaller fragments that can be used to build-up the final target.
In the case of oligomers such as peptides,
oligosaccharides or oligonucleotides, the choice is
obvious: the constituent monomers are the building
blocks, and the synthesis requires the junction of those
monomers by condensation.
Two functional groups, one for each monomer, are involved
in the reaction
What is Development?
Broad range-between research and production-and
overlaps with both
In API (Active Pharmaceutical Ingredient) manufacture,
begins when active substance is identified and activity
demonstrated and more active substance is required.
Once a process that works on plant scale is produced and
is validated, development work still continues to improve
cost, efficiency, quality and environmental impact and to
deal with changing circumstances (vendors, equipment,
new regulations
(FDA21 CFR part11, Risk-Based Approach etc))
19
Broad range-between research and production-and
overlaps with both
In API (Active Pharmaceutical Ingredient) manufacture,
begins when active substance is identified and activity
demonstrated and more active substance is required.
Once a process that works on plant scale is produced and
is validated, development work still continues to improve
cost, efficiency, quality and environmental impact and to
deal with changing circumstances (vendors, equipment,
new regulations
(FDA21 CFR part11, Risk-Based Approach etc))
19
Development Stages
1) Chemical Development
Begins when activity of potential API is demonstrated
and more active substance is required (for clinical trials).
Process research;
–New synthetic routes (literature survey)
–Some initial optimisation
–Yield improvements
–Possibly scale-up to large lab equipment/ kilo lab (up to
about 20 L)
20
1) Chemical Development
Begins when activity of potential API is demonstrated
and more active substance is required (for clinical trials).
Process research;
–New synthetic routes (literature survey)
–Some initial optimisation
–Yield improvements
–Possibly scale-up to large lab equipment/ kilo lab (up to
about 20 L)
20
Development Stages cont’d
2) Process Development
-Optimization (change conditions and parameters)
-Minor change of route / intermediate
-Cheaper / more efficient reagents (new to market)
-Environmentally-friendly reagents and effluent
considerations
-Yield / concentration improvement
-Statistical methods
(e.g. Experimental Design; want maximum amount of unbiased
information about factors affecting a process from as few
observations as possible. Caution -“Facts are stubborn things.
Statistics are more pliable”)
21
2) Process Development
-Optimization (change conditions and parameters)
-Minor change of route / intermediate
-Cheaper / more efficient reagents (new to market)
-Environmentally-friendly reagents and effluent
considerations
-Yield / concentration improvement
-Statistical methods
(e.g. Experimental Design; want maximum amount of unbiased
information about factors affecting a process from as few
observations as possible. Caution -“Facts are stubborn things.
Statistics are more pliable”)
21
Development Stages cont’d
Process Development cont’d
-SCALE-UP (Kilo Lab, Pilot plant trials)
-Transfer to Manufacturing
Parallel synthesis reactor block
-for optimization of condition
22
Process Development cont’d
-SCALE-UP (Kilo Lab, Pilot plant trials)
-Transfer to Manufacturing
Parallel synthesis reactor block
-for optimization of condition
22
Development Stages cont’d
3) Process Support
Further optimisation (continuous improvement)
Fine-tuning of yield and throughput
Cost reduction
Troubleshooting (reworks, reprocessing,
deviations)
New vendor approval (use tests)
Waste minimisation (recycling)
23
3) Process Support
Further optimisation (continuous improvement)
Fine-tuning of yield and throughput
Cost reduction
Troubleshooting (reworks, reprocessing,
deviations)
New vendor approval (use tests)
Waste minimisation (recycling)
23
Chemical Development
Selection of Synthetic Route
GET THE BEST ROUTE FROM THE BEGINNING -Difficult to
change later
Route should be short, efficient, robust and give a high yield
prior to scale-up
Discovery route often not the best. Expedient not optimal. (raw
materials may not be available in bulk, process may not be
efficient and may be safety hazards on large scale)
Compare like with like during selection (Same level of
optimisation and same scale. Are products of same purity
obtained? What is the cost comparison?)
Main constraint is TIME
24
Selection of Synthetic Route
GET THE BEST ROUTE FROM THE BEGINNING -Difficult to
change later
Route should be short, efficient, robust and give a high yield
prior to scale-up
Discovery route often not the best. Expedient not optimal. (raw
materials may not be available in bulk, process may not be
efficient and may be safety hazards on large scale)
Compare like with like during selection (Same level of
optimisation and same scale. Are products of same purity
obtained? What is the cost comparison?)
Main constraint is TIME
24
Chemical Development
Selection of Synthetic Route cont’d
Shortest route usually best (less effluent, shorter lead
time, short plant occupation, less analytical work)
A convergent synthesis will be cheaper than a
divergent (linear) one with the same number of steps
Literature not always correct and perseverance with a
reaction is required
Better to try routes with high chance of success but
those which offer significant benefits should be
attempted even if little precedent
25
Selection of Synthetic Route cont’d
Shortest route usually best (less effluent, shorter lead
time, short plant occupation, less analytical work)
A convergent synthesis will be cheaper than a
divergent (linear) one with the same number of steps
Literature not always correct and perseverance with a
reaction is required
Better to try routes with high chance of success but
those which offer significant benefits should be
attempted even if little precedent
25
Chemical Development
In Convergent Synthesis, sections of the target molecule are prepared and
joined together to form the target molecule. A better yield than a linear
synthesis with the same number of steps will be obtained. The advantage is
significant if the subroutes converge close to the end of the synthesis.
(page 489, “Medicinal Chemistry, An Introduction”, G. Thomas).
26
In Convergent Synthesis, sections of the target molecule are prepared and
joined together to form the target molecule. A better yield than a linear
synthesis with the same number of steps will be obtained. The advantage is
significant if the subroutes converge close to the end of the synthesis.
(page 489, “Medicinal Chemistry, An Introduction”, G. Thomas).
26
Process Development
Optimisation of Synthetic Route –Once Selected
Work up very important
Can steps easily be combined (telescoping)?
Need excellent process control and understanding
of process limits (“stress” the reaction –higher
temperature, longer reaction time, less efficient
mixing). “Critical” steps / parameters (Quality)
Good analytical methods (standards)
Isolate and characterise by-products
A very innocuous process change can often have a
significant influence
27
Optimisation of Synthetic Route –Once Selected
Work up very important
Can steps easily be combined (telescoping)?
Need excellent process control and understanding
of process limits (“stress” the reaction –higher
temperature, longer reaction time, less efficient
mixing). “Critical” steps / parameters (Quality)
Good analytical methods (standards)
Isolate and characterise by-products
A very innocuous process change can often have a
significant influence
27
Costing of Processes
Must be a standard costing procedure
Should be dated and updated
Assumptions should be stated
May be several factors leading to variation –scale,
plant configuration etc.
Compare like with like and be conservative
Carried out by independent person
Want to be able to see which factors increase cost
significantly and why
28
Must be a standard costing procedure
Should be dated and updated
Assumptions should be stated
May be several factors leading to variation –scale,
plant configuration etc.
Compare like with like and be conservative
Carried out by independent person
Want to be able to see which factors increase cost
significantly and why
28
Scale up process
Pharmaceutical Process Scale-Up deals with a
subject both fascinating and vitally important for
the pharmaceutical industry—the procedures of
transferring the results of R&D obtained on
laboratory scale to the pilot plant and finally to
production scale.
29
Pharmaceutical Process Scale-Up deals with a
subject both fascinating and vitally important for
the pharmaceutical industry—the procedures of
transferring the results of R&D obtained on
laboratory scale to the pilot plant and finally to
production scale.
29
Why Scale-up?
Scale up is basically needed for:
Market growth
Introduction of new processes
Reduction in making expensive errors in design
and operation
Concentrate on addressing areas of doubts and
uncertainty
Economic feasibility
30
Scale up is basically needed for:
Market growth
Introduction of new processes
Reduction in making expensive errors in design
and operation
Concentrate on addressing areas of doubts and
uncertainty
Economic feasibility
30
Scale-up
Product and process development for scaling up is typically move in small
steps.
For instance, the development is initially from lab scale to
bench scale then move to pilot scale and finally to
commercialization scale.
By performing scale up step by step, the risk with large
investments could be lessen.
31
Several
Steps
Product and process development for scaling up is typically move in small
steps.
For instance, the development is initially from lab scale to
bench scale then move to pilot scale and finally to
commercialization scale.
By performing scale up step by step, the risk with large
investments could be lessen.
31
Several
Steps
Application of the SELECT
criteria to scale up
Safety
Environmental
Legal
Economic
Control
Throughput
32
criteria to scale up
Safety
Environmental
Legal
Economic
Control
Throughput
32
Application of the SELECT
criteria
Safety
Safety is the number one criteria for research
and development. It describes safety risks
including thermal and reactive hazards, and
toxicity, which become increasingly important
as processes are scaled up.
33
criteria
Safety
Safety is the number one criteria for research
and development. It describes safety risks
including thermal and reactive hazards, and
toxicity, which become increasingly important
as processes are scaled up.
33
Application of the SELECT
criteria Environmental
The pharmaceutical industry follows the
environmental ideals of preventing, minimising and
rendering harmless any reagents used and wastes
generated from processes.
Different metrics are utilised within the industry to
track and minimise environmental impact.
Steps taken to improve environmental credentials for
a process are considered
34
criteria Environmental
The pharmaceutical industry follows the
environmental ideals of preventing, minimising and
rendering harmless any reagents used and wastes
generated from processes.
Different metrics are utilised within the industry to
track and minimise environmental impact.
Steps taken to improve environmental credentials for
a process are considered
34
Application of the SELECT
criteria Legal
It describes legal considerations including
regulation of substances by governments,
environmental legislation and patent law.
35
criteria Legal
It describes legal considerations including
regulation of substances by governments,
environmental legislation and patent law.
35
Application of the SELECT
criteria
Economic
It discusses economic considerations.
36
criteria
Economic
It discusses economic considerations.
36
Application of the SELECT
criteria Control
Quality control is essential for commercial production
of an API (active pharmaceutical ingredient).
Selectivity, stability, purification, registration and
validation of processes, product specifications and
genotoxic impurities all need to be considered to
ensure quality is suitable for market.
37
criteria Control
Quality control is essential for commercial production
of an API (active pharmaceutical ingredient).
Selectivity, stability, purification, registration and
validation of processes, product specifications and
genotoxic impurities all need to be considered to
ensure quality is suitable for market.
37
Application of the SELECT
criteria
Throughput
Making sure that we can produce enough within a given time, where
chemical yields plays an important role, trying to work as concentrated as
possible; if you have one very diluted step in the middle of synthesis this
can really be a bottleneck.
If you have to perform that several steps before the API this might be real
bottleneck and not allow you to make a sufficient volume.
What's quite often used is a telescoping of reactions, meaning you work in
the same solvent for a number of consecutive steps which is really
improving throughput because
-you don't need to isolate intermediates,
-don't need to filter or centrifugate them,
-you don't need to dry them as
-you don't need to bring them again or dissolve them again for the next
step
So, that's one way to really improve throughput..
38
criteria
Throughput
Making sure that we can produce enough within a given time, where
chemical yields plays an important role, trying to work as concentrated as
possible; if you have one very diluted step in the middle of synthesis this
can really be a bottleneck.
If you have to perform that several steps before the API this might be real
bottleneck and not allow you to make a sufficient volume.
What's quite often used is a telescoping of reactions, meaning you work in
the same solvent for a number of consecutive steps which is really
improving throughput because
-you don't need to isolate intermediates,
-don't need to filter or centrifugate them,
-you don't need to dry them as
-you don't need to bring them again or dissolve them again for the next
step
So, that's one way to really improve throughput..
38
Summary: Application of the SELECTcriteria
39
Criteria Sub-criteria Examples of Potential Issues
Safety
Process safety Explosions
Exposure to harmful substancesCarcinogens, sensitisers
Environmental
Wasted resources Quantity & variety of solvents
Substances harmful to the
environment
Aquatic toxins, ozone depleters
Legal
Infringement of Intellectual Property
Competitor patenting key
intermediate
Regulation of reagents and
intermediates
Economic
Meeting Cost of Good (profit
margin)
Long synthesis or expensive starting
materials
Investment costs (equipment)
Control
Control of quality Meeting specifications/ GMP
Control of physical/chemical
parameters
Throughput
Time scale of manufacture Long synthetic route
Availability of starting materials Rare natural products
39
Criteria Sub-criteria Examples of Potential Issues
Safety
Process safety Explosions
Exposure to harmful substancesCarcinogens, sensitisers
Environmental
Wasted resources Quantity & variety of solvents
Substances harmful to the
environment
Aquatic toxins, ozone depleters
Legal
Infringement of Intellectual Property
Competitor patenting key
intermediate
Regulation of reagents and
intermediates
Economic
Meeting Cost of Good (profit
margin)
Long synthesis or expensive starting
materials
Investment costs (equipment)
Control
Control of quality Meeting specifications/ GMP
Control of physical/chemical
parameters
Throughput
Time scale of manufacture Long synthetic route
Availability of starting materials Rare natural products
OBJECT
IVE
40
Stages of Scale up process
IVE
40
Stages of Scale up process
41
Stages of Scale up process
Stages of Scale up process
Planning for Scale up
Decide on process
Decide on batch size (not too large an increase)
Order raw materials (allow for 10% lower yield)
Carry out safety tests (Exotherms, HAZOP –hazard and
operability studies)
Discuss the process and plant requirements with
production manager/engineer (materials of
construction). Existing multipurpose plant usually.
Prepare safety data sheets and discuss handling of
hazardous reagents or intermediates
Ensure analytical procedures, equipment and staff are
available
42
Decide on process
Decide on batch size (not too large an increase)
Order raw materials (allow for 10% lower yield)
Carry out safety tests (Exotherms, HAZOP –hazard and
operability studies)
Discuss the process and plant requirements with
production manager/engineer (materials of
construction). Existing multipurpose plant usually.
Prepare safety data sheets and discuss handling of
hazardous reagents or intermediates
Ensure analytical procedures, equipment and staff are
available
42
Planning for Scale up cont’d
Write out detailed procedure (assume nothing);
Cleaning check and preparative work
Charging and weighing
Temperature and time limits
Sampling (in-process checks)
Transfers
Work-up and isolation
Drying and effluent disposal/treatment
Make allowance for delays / problems (rework procedures,
identify suitable “hold points”)
43
Write out detailed procedure (assume nothing);
Cleaning check and preparative work
Charging and weighing
Temperature and time limits
Sampling (in-process checks)
Transfers
Work-up and isolation
Drying and effluent disposal/treatment
Make allowance for delays / problems (rework procedures,
identify suitable “hold points”)
43
Planning for Scale up cont’d
Leave space in procedure to record data and
observations
Highlight safety procedures and steps to take if
spillage occurs
Provide training
44
Leave space in procedure to record data and
observations
Highlight safety procedures and steps to take if
spillage occurs
Provide training
44
Planning for Scale up cont’d
Significant Differences Between Lab and Plant
Heat transfer
Agitation (frothing)
Mass transfer (affects kinetics)
Visibility –of reactions, separations, for cleanliness checks
Separation (stirring, not shaking)
Time (slower additon rates and heating/cooling times,
longer work up)
Hazards (Toxic, Exotherm and Electrostatic)
Off-gas treatment
Safe and efficient sampling techniques needed (Process
Analytical Technology -Real time reaction monitoring; FT-IR,
Particle size, etc.)
45
Significant Differences Between Lab and Plant
Heat transfer
Agitation (frothing)
Mass transfer (affects kinetics)
Visibility –of reactions, separations, for cleanliness checks
Separation (stirring, not shaking)
Time (slower additon rates and heating/cooling times,
longer work up)
Hazards (Toxic, Exotherm and Electrostatic)
Off-gas treatment
Safe and efficient sampling techniques needed (Process
Analytical Technology -Real time reaction monitoring; FT-IR,
Particle size, etc.)
45
Planning for Scale up cont’d
Process Development Taking Account of Differences Between Lab and
Plant Equipment
Use safety data already produced to help characterise
reaction
Study effect of scale-dependent factors (mixing, mass
transfer and heat transfer) at lab scale
Plan a logical set of experiments in time-frame available
Mimic plant conditions; slower addition of reagents, slower
rate of heat increase and decrease and mixing, lab system
should be baffled if reactors are (no vortex)
Obtain mass and heat transfer data for reactor type, agitator
type and solvents to be used.
Use simulation software to predict effects of mass and heat
transfer and mixing changes on scale-up.
46
Process Development Taking Account of Differences Between Lab and
Plant Equipment
Use safety data already produced to help characterise
reaction
Study effect of scale-dependent factors (mixing, mass
transfer and heat transfer) at lab scale
Plan a logical set of experiments in time-frame available
Mimic plant conditions; slower addition of reagents, slower
rate of heat increase and decrease and mixing, lab system
should be baffled if reactors are (no vortex)
Obtain mass and heat transfer data for reactor type, agitator
type and solvents to be used.
Use simulation software to predict effects of mass and heat
transfer and mixing changes on scale-up.
46
Essential steps
47
Laboratory
Mock-UPS
(Source: Euzen et al., 1993)
47
Laboratory
Mock-UPS
(Source: Euzen et al., 1993)
Production Capacity
Table below shows the general production capacity of each scaling
up step in the process industries.
48
Scaling factor Typical production
capacity
Bench/ Laboratory 0.001 –0.1 kg/h
Pilot Plant 10 –100 kg/h
Demonstration Plant 100 –1000 kg/h
Commercial Plant > 1000 kg/h
Table below shows the general production capacity of each scaling
up step in the process industries.
48
Scaling factor Typical production
capacity
Bench/ Laboratory 0.001 –0.1 kg/h
Pilot Plant 10 –100 kg/h
Demonstration Plant 100 –1000 kg/h
Commercial Plant > 1000 kg/h
Steps in process
Development
49
Development
49
The collection and evaluation of data, from the
process design stage through commercial
production, which establishes scientific evidence that
a process is capable of consistentlydelivering quality products.
(FDA)
Documented evidencewhich provides a high degree of
assurance that a specific process will
consistentlyresult in a product that meets
predetermined specifications and quality
characteristics. (WHO)
The documented evidencethat the process,
operated within established parameters, can
perform effectivelyand reproduciblyto produce a
medicinal product meeting its predetermined
specifications and quality attributes.
50
Validation of Large scale Process
process design stage through commercial
production, which establishes scientific evidence that
a process is capable of consistentlydelivering quality products.
(FDA)
Documented evidencewhich provides a high degree of
assurance that a specific process will
consistentlyresult in a product that meets
predetermined specifications and quality
characteristics. (WHO)
The documented evidencethat the process,
operated within established parameters, can
perform effectivelyand reproduciblyto produce a
medicinal product meeting its predetermined
specifications and quality attributes.
50
Validation of Large scale Process
Validation of Large scale Process
Traditional vs new paradigm
Post approval
changes/chan
ge
controls/risk
analysis
Development-
Basic
Process
validation-
3 batches
Pilot batch
manufacturing
Enhanced-
Development
and
process
qualification
Control
Strategy
ICH
Q8,
QbD
Continuous and
extensive
monitoring of
CQAs and
CPPs for each
production
batch
ICH Q9
and Q10
51
Traditional vs new paradigm
Post approval
changes/chan
ge
controls/risk
analysis
Development-
Basic
Process
validation-
3 batches
Pilot batch
manufacturing
Enhanced-
Development
and
process
qualification
Control
Strategy
ICH
Q8,
QbD
Continuous and
extensive
monitoring of
CQAs and
CPPs for each
production
batch
ICH Q9
and Q10
51
52
Pre-validation
phase
Protocol
Preparation
Information from
product
development
studies
(identification of
critical
attributes)
Information from
primary/ clinical
manufacturing
(scale up
information)
Process risk
assessment
information
(identification of
critical steps)
Validation phase
Protocol
execution
Includes
demonstration of
content uniformity
of the clinical
batch
Process validation phases
Post valdnphase:
Review of process,
deviations, failures,
need for
improvement, scale
up etc…
Pre-validation
phase
Protocol
Preparation
Information from
product
development
studies
(identification of
critical
attributes)
Information from
primary/ clinical
manufacturing
(scale up
information)
Process risk
assessment
information
(identification of
critical steps)
Validation phase
Protocol
execution
Includes
demonstration of
content uniformity
of the clinical
batch
Process validation phases
Post valdnphase:
Review of process,
deviations, failures,
need for
improvement, scale
up etc…
FDA, January 2011 WHO, Revised Annex 7 of
WHO GMP guide (draft for
comment)
European Medicines Agency
(EMA), February 2014
Continuous process
verification (CPV)
Continuous process verification
(CPV)
Alternative approaches:
-Traditional approach
-Continuous process
verification
-Hybrid approach
Process design and Initial
validation (process
qualification-PPQ)are initial
phases of CPV
Process design and initial
validation (initial process
verification)are initial phases of
CPV
CPV protocol to be supported
by extensive dev. information
and lab or pilot scale data.
Executed on each production
batch
No mention of number of
batches for initial process
performance qualification /
validation (rather must be
justified based on overall
product and process
understanding)
Mentions data on at least three
pilot or production batches
collected as part of process
design
Number of batches specified
for traditional approach
-minimum of three production
batches unless other wise
justified
53
Latest guidelines
WHO GMP guide (draft for
comment)
European Medicines Agency
(EMA), February 2014
Continuous process
verification (CPV)
Continuous process verification
(CPV)
Alternative approaches:
-Traditional approach
-Continuous process
verification
-Hybrid approach
Process design and Initial
validation (process
qualification-PPQ)are initial
phases of CPV
Process design and initial
validation (initial process
verification)are initial phases of
CPV
CPV protocol to be supported
by extensive dev. information
and lab or pilot scale data.
Executed on each production
batch
No mention of number of
batches for initial process
performance qualification /
validation (rather must be
justified based on overall
product and process
understanding)
Mentions data on at least three
pilot or production batches
collected as part of process
design
Number of batches specified
for traditional approach
-minimum of three production
batches unless other wise
justified
53
Latest guidelines
Prospective validation Concurrent validation Retrospective validation
Protocol reviewed and
accepted, Product PQD; OR
Protocol executed before
submission or PQ
Protocol reviewed and
accepted, Product PQD
Protocol does not need to be
submitted
Execute and finalize process
validation on the first three
production batches
Execute and finalize process
validation on the first three
production batches
Prepare product quality
review report on already
manufactured production
batches
Commercial batches to be
released only after
satisfactorily conclusion of
process validation on three
batches
Each validation batch can be
validated and released.
Applicable for low demand
products (such as NTDs,
orphan drugs or other
seasonal products)
Applicable for submissions
meeting criteria for
established products as
described in Annex 4, TRS
970
54
Types of process validation and
dossier requirements
Protocol reviewed and
accepted, Product PQD; OR
Protocol executed before
submission or PQ
Protocol reviewed and
accepted, Product PQD
Protocol does not need to be
submitted
Execute and finalize process
validation on the first three
production batches
Execute and finalize process
validation on the first three
production batches
Prepare product quality
review report on already
manufactured production
batches
Commercial batches to be
released only after
satisfactorily conclusion of
process validation on three
batches
Each validation batch can be
validated and released.
Applicable for low demand
products (such as NTDs,
orphan drugs or other
seasonal products)
Applicable for submissions
meeting criteria for
established products as
described in Annex 4, TRS
970
54
Types of process validation and
dossier requirements
Design Qualification( DQ)
verification process to meet
particular requirement relating to
the quality of Pharmaceutical and
manufacturing process.
55
Process validation-Role of assessment
Design
qualificat
ion
Operatio
nal
qualificati
on
Performa
nce
qualificati
on
Process
validatio
n
GMP
Dossier
Performance qualification (PQ)(process
qualification)-process of testing to ensure that the
individual and combined systems function to meet
agreed performance criteria on a consistent basis
and to check how the result of testing is recorded.
The purpose is to ensure that the criteria specified
can be achieved on a reliable basis over a period of
time.
Operational Qualification (OQ)process of
testing to ensure individual and combined
systems function to meet agreed performance
criteria and to check how the result of testing
is recorded. The purpose is to ensure that all
the dynamic attributes comply with the
original design.
DQ plan covers user requirement,
user specification, Technical
specification and DQ report.
Process Validation :-Owners are responsible for Validating Their Processes (personnel,
equipment, methods, SOPs) to ensure compliance to cGMP/GLP regulations.
verification process to meet
particular requirement relating to
the quality of Pharmaceutical and
manufacturing process.
55
Process validation-Role of assessment
Design
qualificat
ion
Operatio
nal
qualificati
on
Performa
nce
qualificati
on
Process
validatio
n
GMP
Dossier
Performance qualification (PQ)(process
qualification)-process of testing to ensure that the
individual and combined systems function to meet
agreed performance criteria on a consistent basis
and to check how the result of testing is recorded.
The purpose is to ensure that the criteria specified
can be achieved on a reliable basis over a period of
time.
Operational Qualification (OQ)process of
testing to ensure individual and combined
systems function to meet agreed performance
criteria and to check how the result of testing
is recorded. The purpose is to ensure that all
the dynamic attributes comply with the
original design.
DQ plan covers user requirement,
user specification, Technical
specification and DQ report.
Process Validation :-Owners are responsible for Validating Their Processes (personnel,
equipment, methods, SOPs) to ensure compliance to cGMP/GLP regulations.
Case study; Process Development for
Labetalol Production
BACKGROUND
Labetalol –antihypertensive, 30,000 Kg p.a. produced by
Schering-Plough.
Labetalol Manufacturing Process
Mono-pot reaction in jacketed, glass-lined 10,000 L reactor.
Addition of liquid reagents and jacket temperature computer
controlled. Solid reagents charged manually via handwhole.
Phase separation using sight-glass.
Solid product from second step isolated by centrifugation.
Product tested to determine if recrystallisationnecessary.
When required purity achieved, product is dried
56
Labetalol Production
BACKGROUND
Labetalol –antihypertensive, 30,000 Kg p.a. produced by
Schering-Plough.
Labetalol Manufacturing Process
Mono-pot reaction in jacketed, glass-lined 10,000 L reactor.
Addition of liquid reagents and jacket temperature computer
controlled. Solid reagents charged manually via handwhole.
Phase separation using sight-glass.
Solid product from second step isolated by centrifugation.
Product tested to determine if recrystallisationnecessary.
When required purity achieved, product is dried
56
Labetalol Process –Step 1
Solvent system modified to isopropanol / ethyl acetate containing hydrogen
bromide from methanol / ethyl acetate to reduce formation of third impurity.
Original process used chloroform.
Concentration was increased threefold increasing throughput and reducing
solvent waste.
57
Main Impurities
Solvent system modified to isopropanol / ethyl acetate containing hydrogen
bromide from methanol / ethyl acetate to reduce formation of third impurity.
Original process used chloroform.
Concentration was increased threefold increasing throughput and reducing
solvent waste.
57
Main Impurities
Labetalol Process –Step 2
Process Development
Large excess of dibenzylamine used to ensure reaction driven to completion (cheap reagent and easily
washed out)
Propylene oxide added as it reacts with HBr side-product as it’s produced. Presence of HBr would neutralise
dibenzylamine and no reaction to give product would occur. Propylene bromohydrin side-product easily
washed out.
Use gentle reflux to ensure propylene oxide doesn’t escape
58
+
Process Development
Large excess of dibenzylamine used to ensure reaction driven to completion (cheap reagent and easily
washed out)
Propylene oxide added as it reacts with HBr side-product as it’s produced. Presence of HBr would neutralise
dibenzylamine and no reaction to give product would occur. Propylene bromohydrin side-product easily
washed out.
Use gentle reflux to ensure propylene oxide doesn’t escape
58
+
Summary
Stages of development are Chemical Development, Process Development and Process
Support
Development essential before scale-up and validation –get process right
first
Time constraints a major factor
Have process in control (“critical” parameters)
Consider differences between lab and plant scale. Try to mimic plant
conditions in lab to anticipate effects when scale up.
Prepare process description carefully for scale-up
Development always on-going
59
Stages of development are Chemical Development, Process Development and Process
Support
Development essential before scale-up and validation –get process right
first
Time constraints a major factor
Have process in control (“critical” parameters)
Consider differences between lab and plant scale. Try to mimic plant
conditions in lab to anticipate effects when scale up.
Prepare process description carefully for scale-up
Development always on-going
59
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